Molecular Mechanisms of Obesity in Children Exposed to Phthalates in Utero

子宫内接触邻苯二甲酸盐的儿童肥胖的分子机制

基本信息

批准号：
8496565
负责人：
Nina T Holland
金额：
$ 63.29万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496565
关键词：
14 year old 9 year old Address Adolescence Adolescent Affect Age Agriculture Animal Model Animals Bioinformatics Biological Biological Markers Birth Blood Candidate Disease Gene Cell model Child Child health care Childhood Collection Cosmetics DNA Methylation Data Development Diet Disease Elderly Endocrine Disruptors Energy Intake Energy Metabolism Enrollment Environmental Exposure Epidemic Epidemiologic Studies Epigenetic Process Etiology Exposure to Functional RNA Future Gene Expression Genes Genetic Predisposition to Disease Goals Growth Health High Prevalence Hormones Human In Vitro Interdisciplinary Study Isoprostanes Latino Lead Leptin Link Measures Mediating Metabolic Metabolic syndrome Methodology Methylation Mexican Americans Minority Modification Molecular Mothers National Health and Nutrition Examination Survey Not Hispanic or Latino Obesity Outcome Overweight Oxidative Stress Participant Pattern Perinatal Exposure Peroxisome Proliferator-Activated Receptors Physical activity Plastics Policies Population Pregnancy Pregnant Women Prevalence Proteins Puberty Race Rat Cell Line Research Role Salinum Sampling Site United States Urine adipokines adiponectin bisulfite cohort critical period early adolescence early life exposure environmental chemical epigenetic marker genome-wide high risk histone modification improved in utero lifestyle factors lipid biosynthesis methylome next generation obesity in children obesity risk obesogen phthalates prenatal prevent programs public health relevance response sex social waist circumference

项目摘要

DESCRIPTION (provided by applicant): In the last 30 years, the prevalence of obesity has risen sharply among children, and minority populations are particularly vulnerable. In the CHAMACOS birth cohort, a Mexican-American population from the agricultural Salinas Valley, CA, children have a particularly high prevalence of obesity (>39% at age 9) compared to both Mexican-American children (25%) and children of all races (20%) in the United States. Changes in diet and physical activity patterns do not completely explain the current obesity epidemic. Recent research suggests that exposure to environmental obesogens, particularly during the prenatal period, may also contribute to increases in obesity. Evidence from animals and epidemiologic studies suggests that phthalates, components of plastics and cosmetics ubiquitously found in humans, may be obesogenic. For instance, as shown in animals, they can change levels of biomarkers of obesity such as adipokines, protein hormones that regulate adipogenesis. There is also growing evidence that environmental exposures can influence DNA methylation (one of the main types of epigenetic markers) and result in adverse health outcomes. However, to date, no data are available on the effects of prenatal phthalate exposure on the molecular mechanisms of obesity in children or the potential role of epigenetic dysregulation. The overall goal of this proposal is to determine whether prenatal phthalate exposure contributes to the development of childhood obesity and metabolic syndrome (MetS) and to examine whether epigenetic changes mediate this relationship. We hypothesize that in utero phthalate exposure alters DNA methylation and leads to changes in adipokines (adiponectin and leptin), oxidative stress (isoprostanes), and higher risk of obesity and metabolic MetS in children. First, we will assess whether early and/or late pregnancy exposures are associated with a) biomarkers (adiponectin, leptin and isoprostane) and b) parameters of obesity and MetS in children at 5, 9 and 14 years of age. Second, we will characterize DNA methylation patterns in children at birth and 9 years of age, and examine whether site-specific changes in the methylome (by 450K array) are associated with a) prenatal phthalate exposure and b) biomarkers and parameters of obesity and MetS. Finally, we will validate 450K array data using next generation bisulfite sequencing and the most advanced expression and bioinformatic methodologies. The proposed research utilizes the rich collection of biological samples and data on exposures, diet, activities, and health outcomes in CHAMACOS participants. By extending assessment of children to age 14, this study will include critical periods of obesity development spanning pregnancy through adolescence. Our results will help elucidate the longitudinal effects of phthalates on obesity, explore the role of epigenetics and adipokines in the development of obesity and MetS, and address important gaps in our understanding of obesity. They will also inform policies aimed at improving children's health and preventing child obesity.

描述（由申请人提供）：过去 30 年来，儿童肥胖患病率急剧上升，少数族裔尤其容易受到影响。在 CHAMACOS 出生队列中，来自加利福尼亚州萨利纳斯谷农业区的墨西哥裔美国人中，与墨西哥裔美国儿童 (25%) 和所有其他国家的儿童相比，儿童的肥胖患病率特别高（9 岁时>39%）。美国的比赛（20%）。饮食和身体活动模式的变化并不能完全解释当前的肥胖流行。最近的研究表明，接触环境致肥胖物质，特别是在产前时期，也可能导致肥胖增加。来自动物和流行病学研究的证据表明，人类体内普遍存在的塑料和化妆品成分邻苯二甲酸盐可能会导致肥胖。例如，如动物实验所示，它们可以改变肥胖生物标志物的水平，例如脂肪因子、调节脂肪生成的蛋白质激素。还有越来越多的证据表明，环境暴露会影响 DNA 甲基化（表观遗传标记的主要类型之一）并导致不良的健康结果。然而，迄今为止，还没有关于产前邻苯二甲酸盐暴露对儿童肥胖分子机制的影响或表观遗传失调的潜在作用的数据。该提案的总体目标是确定产前邻苯二甲酸盐暴露是否会导致儿童肥胖和代谢综合征 (MetS) 的发生，并检查表观遗传变化是否介导这种关系。我们假设，子宫内邻苯二甲酸盐暴露会改变 DNA 甲基化，并导致脂肪因子（脂联素和瘦素）、氧化应激（异前列腺素）的变化以及儿童肥胖和代谢性代谢综合征的更高风险。首先，我们将评估 5、9 和 14 岁儿童中妊娠早期和/或晚期暴露是否与 a) 生物标志物（脂联素、瘦素和异前列腺素）和 b) 肥胖和 MetS 参数相关。其次，我们将表征儿童出生时和 9 岁时的 DNA 甲基化模式，并检查甲基化组（通过 450K 阵列）的位点特异性变化是否与 a) 产前邻苯二甲酸盐暴露和 b) 肥胖和肥胖的生物标志物和参数相关。气象局。最后，我们将使用下一代亚硫酸氢盐测序以及最先进的表达和生物信息学方法来验证 450K 阵列数据。拟议的研究利用了 CHAMACOS 参与者丰富的生物样本和暴露、饮食、活动和健康结果的数据。通过将儿童的评估范围扩大到 14 岁，这项研究将包括从怀孕到青春期肥胖发展的关键时期。我们的研究结果将有助于阐明邻苯二甲酸盐对肥胖的纵向影响，探索表观遗传学和脂肪因子在肥胖和代谢综合征发展中的作用，并解决我们对肥胖理解中的重要差距。他们还将为旨在改善儿童健康和预防儿童肥胖的政策提供信息。